The effect of dietary soy supplementation compared to estrogen and

Maturitas 67 (2010) 262–269
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Maturitas
journal homepage: www.elsevier.com/locate/maturitas
The effect of dietary soy supplementation compared to estrogen and placebo on
menopausal symptoms: A randomized controlled trial
Lucio O. Carmignani, Adriana Orcesi Pedro ∗ , Lucia H. Costa-Paiva, Aarão M. Pinto-Neto
Department of Obstetrics and Gynecology, State University of Campinas, Brazil
a r t i c l e
i n f o
Article history:
Received 9 December 2009
Received in revised form 29 June 2010
Accepted 15 July 2010
Keywords:
Menopause
Soy
Menopause Rating Scale
Randomized
Controlled trial
Hormone therapy
a b s t r a c t
Objectives: To compare the effects of daily ingestion of dietary soy supplementation, low-dose hormone
therapy (HT) and placebo on psychological, somatic and urogenital symptoms in postmenopausal women.
Study design: A double-blind, randomized, controlled trial. Sixty healthy, symptomatic, postmenopausal
women of 40–60 years of age were allocated to use dietary soy supplementation (containing 90 mg of
isoflavone) or HT (1 mg estradiol and 0.5 mg norethisterone acetate) or placebo. Main outcome measures:
the Menopause Rating Scale (MRS) was used to assess menopausal symptoms at baseline and after 16
weeks of treatment. Intention-to-treat analyses were performed using the chi-square test, Fisher’s exact
test, the Kruskal–Wallis non-parametric test and analysis of variance (ANOVA).
Results: No statistically significant differences were found between the groups with respect to baseline
clinical and sociodemographic characteristics. The psychological, somatic and urogenital symptoms analyzed in the MRS improved during treatment in all the groups, except for urogenital symptoms in the
placebo group in which no significant changes were detected. Comparison between groups revealed a statistically significant improvement in somatic symptoms (hot flashes and muscle pain) in the users of HT
(−45.6%) and dietary soy supplementation (−49.8%). Urogenital symptoms (vaginal dryness) improved
significantly in HT users (−38.6%) and in users of the dietary soy supplementation (−31.2%). There was
no statistically significant difference between the groups with respect to overall MRS score or to scores
obtained in the psychological symptoms subscale.
Conclusion: Dietary soy supplementation may constitute an effective alternative therapy for somatic and
urogenital symptoms of the menopause.
© 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Approximately 80% of menopausal women experience climacteric symptoms that negatively affect their quality of life [1].
A population-based study conducted in Brazil reported a prevalence of hot flashes of approximately 70% in perimenopausal and
postmenopausal women [2]. Hormone therapy (HT) has been
well-established for the treatment of climacteric symptoms in postmenopausal women; however, recent reports have shown that
exposure to hormone therapy may increase women’s risk of breast
cancer, coronary heart disease, stroke and pulmonary embolism [3].
Therefore, since the risks of hormone therapy for the relief of postmenopausal symptoms may outweigh the benefits in some cases,
alternatives to HT are being investigated. In Brazil, a recent evaluation of the Women’s Health Initiative (WHI), which assessed the
∗ Corresponding author at: Department of Obstetrics and Gynecology, UNICAMP,
Rua Alexander Fleming, 101, 13083-881Campinas, SP, Brazil.
Tel.: +55 19 3254 1157; fax: +55 19 3254 1157.
E-mail address: [email protected] (A.O. Pedro).
0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2010.07.007
medical knowledge of gynecologists with respect to the menopause
and the treatment of symptomatic women, and the repercussions of
this knowledge on their attitudes and practice, reported that 46.3%
of gynecologists had begun to prescribe isoflavone and other natural therapies for menopausal symptoms [4]. Many women consider
the risk associated with hormone therapy to be unacceptable and
request non-hormonal alternatives for the management of their
vasomotor symptoms.
Interest has arisen concerning isoflavones, found in abundance
in soy products, for the treatment of hot flashes [5]. Although
many factors may contribute to the low prevalence of vasomotor
symptoms in postmenopausal women in some Asian cultures, one
possible explanation may be a diet high in phytoestrogens, plant
compounds with estrogen-like properties [6]. Soy is a rich source
of the isoflavones genistein, daidzein and glycitein. Isoflavones are
structurally similar to estradiol and have a high binding affinity
for the beta-estrogen receptor. The diphenolic structure of lignans
and isoflavones is similar to that of 17␤-estradiol and these compounds are believed to have estrogenic or antiestrogenic effects,
depending on circulating estrogen levels, i.e. they act as antiestrogens when estrogen levels are high and as estrogens when
L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
estrogen levels are low as in the case of postmenopausal women
[7].
Clinical studies have shown that a soy isoflavone extract
successfully improved menopausal symptoms [8]. However,
other studies have failed to demonstrate any improvement in
menopausal symptoms with daily isoflavone doses of 80 mg or
more in postmenopausal patients [9]. Studies indicating an inconclusive effect on symptoms have also often shown a bias in
methodology; for example, in some studies the populations consisted of both perimenopausal and postmenopausal women [10];
some studies used soy powders that were found to provoke gastrointestinal side effects, resulting in high dropout rates [10,11];
not all studies were placebo-controlled and others failed to control
phytoestrogen intake from other food sources, leading to potential
contamination [10–12].
Therefore, the purpose of this study was to determine the effects
of a single soy protein dietary supplement containing 90 mg of
isoflavone on psychological, somatic and urogenital symptoms
in postmenopausal women, and to compare the results with the
effects of low-dose hormone therapy and placebo.
2. Methods
2.1. Study participants
Sixty participants were recruited from two menopause outpatient clinics situated at the Center for Women’s Integrated
Healthcare of the University of Campinas (UNICAMP), Campinas,
São Paulo, Brazil, and at the Leonor Mendes de Barros Maternity Hospital in São Paulo, Brazil to participate in a 16-week double-blind,
randomized, placebo-controlled trial designed to examine the
effects of a dietary soy isoflavone supplementation on menopausal
symptoms.
Inclusion criteria consisted of postmenopausal women between
40 and 60 years of age who had their last menstrual period more
than 12 months previously, had follicle-stimulating hormone (FSH)
levels >30 mUI/ml and estradiol levels <20 pg/ml, who were having more than 8 hot flashes in 24 h, had not been using any form
of hormonal treatment during the previous 6 months and were
not currently using any lipid-lowering drugs, antidiabetic drugs,
soybean derived products or herbal supplements. The exclusion
criteria consisted of: previous hysterectomy, chronic gastrointestinal disorder, any contraindication to hormone therapy or patients
participating in a conflicting clinical trial. Finally, women were
excluded if they had a known allergy or hypersensitivity to soy or
cow milk or were not willing to cease consumption of soy products
for the 16 weeks of the study. The study was conducted between
January and October 2007. The Internal Review Board of the institution approved the protocol, and all participants signed an informed
consent form.
2.2. Randomization and blinding
After initial recruitment, 60 women were successfully screened
and randomly assigned to one of the three different treatment
groups in a sequence determined by a computer-generated randomization list. A numerically randomized envelope containing a
label that indicated #1, #2 or #3, corresponding to the patient’s
allocation to the hormone therapy, isoflavone 90 mg per day or
placebo groups, respectively, was opened for each patient. For the
duration of the study, the subjects and study personnel remained
blinded with respect to the treatment modality. Study drugs were
packaged in bottles containing sufficient treatment for 30 days. A
gynecologist who did not participate in the screening process of this
study or in dispensing the drugs conducted the patient follow-up.
263
2.3. Intervention
The three treatment groups consisted of the following therapies:
• Hormone therapy (n = 20): one tablet containing 1 mg of estradiol and 0.5 mg of norethisterone acetate (Activelle® , Medley
Pharmaceuticals, Campinas, São Paulo, Brazil), in addition to 2
portions/day of placebo powder.
• Soy group (n = 20): one placebo tablet plus 2 portions/day
of dietary soy supplementation powder containing 45 mg of
isoflavone per portion, making a total of 90 mg of isoflavone/day
(Previna® , Sanavita Functional Foods, Piracicaba, São Paulo,
Brazil).
• Placebo group (n = 20): one placebo tablet and 2 portions/day of
placebo powder.
The dietary soy supplement (Previna® , Sanavita Functional
Foods, Piracicaba, SP, Brazil) consisted of 20 g portions of a food
powder containing 12 g of soy protein and a total of 45 mg
of isoflavones (26.5 mg aglycons) to be mixed with 200 ml of
water. The soy supplement contained approximately 8 mg of total
daidzein, 15 mg total genistein and 3.5 mg total glycitein. The
placebo powder (Sanavita Functional Foods) contained 20 g of maltodextrin, was identical in appearance to the soy powder and
contained the same nutrients and calories except for the isoflavones
and soy protein. Both supplements also contained 488 mg of calcium carbonate and 1.2 mg of hydrolyzed collagen per portion. The
supplement was taken twice a day for a total of 16 weeks.
The placebo tablet was taken once a day. It was identical in
appearance to the hormone therapy tablet and was produced by
Medley Pharmaceuticals.
2.4. Measurements
At the screening visit, women completed a standardized questionnaire designed to obtain information on their demographic
characteristics including age, ethnicity, education level and social
status. Women were also queried about their reproductive history,
age at menopause, time since menopause, use of medication, history of cigarette smoking and frequency of alcohol consumption.
In all three groups, data were collected at baseline and after 16
weeks of use of the respective medication. To examine the effects
of the regime on endogenous hormone levels, follicle-stimulating
hormone (FSH) and 17␤-estradiol were measured. The Menopause
Rating Scale (MRS) was used to evaluate menopausal symptoms at
baseline and after 16 weeks of treatment. The MRS is composed of
11 items assessing menopausal symptoms and is divided into three
subscales [13]:
• Somatic symptoms: hot flashes, heart discomfort, sleeping
problems and muscle and joint problems (items 1–3 and 11,
respectively).
• Psychological symptoms: depressive mood, irritability, anxiety,
physical and mental exhaustion (items 4–7, respectively).
• Urogenital symptoms: sexual problems, bladder problems and
vaginal dryness (items 8–10, respectively).
Each item is graded by the subject, scores ranging from zero
(absent) to four (1 = mild; 2 = moderate; 3 = severe; 4 = very severe).
The total score for each subscale is the sum of each item graded
within that subscale. Total MRS score is composed of the sum of
the scores obtained for each subscale.
Side effects were analyzed according to the occurrence or exacerbation of an adverse event during the treatment period. If the
event was already present prior to admission to the study and either
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L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
persisted unchanged or improved within the treatment period, it
was considered to have remained unaltered.
Transvaginal sonography was performed to evaluate endometrial thickness. The endometrial stripe was measured at its
maximum anteroposterior thickness along the longitudinal axis
(1/3) of the uterine body from the echogenic interface of the
endometrial–myometrial junction on both sides. The operator who
performed all the exams did not know patient clinical data.
Vaginal smears were obtained from the lateral vaginal wall using
an Ayre spatula and stained according to the Papanicolaou technique. The maturation index was scored under a light microscope
by a single cytopathologist blinded to the study group at the baseline and after treatment. The maturation value (MV) was calculated
by the following way: Superficial cells were assigned a point value
of 1.0, intermediate cells were assigned a point value of 0.5, and
parabasal cells were assigned a point value of 0. The number of
cells in each category was multiplied by the point value, and the
three results were added to calculate the MV.
2.5. Compliance
Compliance was assessed according to the patient’s self-report
of the number of packages of the product that she had omitted
to take, this figure then being converted to a percentage of the
prescribed packages that were ingested.
2.6. Statistical analysis
Data were analyzed according to the intention-to-treat principle, and included all the original participants in the group to
which they were randomly assigned. Data referring to patients’
epidemiological and clinical characteristics were analyzed using
the chi-square test, Fisher’s exact test, the Kruskal–Wallis nonparametric test and analysis of variance (ANOVA). The scores
obtained in the MRS and its subscales were analyzed as means.
The observations recorded at baseline were then compared with
those recorded for the same patient at the end of treatment,
inter-group comparisons being evaluated using the paired Student’s t test. The mean percentage variation between groups
was compared using the Kruskal–Wallis test followed by the
Mann–Whitney test. The percent variation was calculated using the
formula: pretreatment value − post-treatment value/pretreatment
value × 100. The menopausal symptoms comprising each MRS subscale were analyzed according to the mean percentage variation
using the Kruskal–Wallis test followed by the Mann–Whitney
test. The mean percentage variation in estradiol and FSH levels was calculated using ANOVA followed by the Tukey test and
using the Kruskal–Wallis non-parametric test followed by the
Mann–Whitney test. Side effects were analyzed using Fisher’s exact
test. An alpha error of 0.05 was chosen; only p-values <0.05 were
considered significant. The software program used to perform all
the statistical analyses was SAS, version 9.1.3 (SAS Institute Inc.,
Carey, NC, USA).
2.7. Sample size
Calculation of sample size indicated that 16 subjects were
required in each group to reach a power of 90% in the detection
of differences between the three treatment modalities, assuming
a difference of three hot flashes in a 24-h period and a standard
deviation of 3.8 hot flashes per day. The test was performed with a
significance level of ˛ 0.05 and ˇ 0.05, based on a study by Albertazzi et al. [10], 1998. The total number of subjects per group was
increased to 20 (an increase of more than 20%) to compensate for
any possible lost-to-follow-up [14].
Calculation of sample size was determined on the basis of the
comparison between the phytoestrogen group and the control
group. This option was selected because a much smaller sample
size would have resulted if the difference between the HT and
the control group had been selected, since according to the literature this latter comparison implies in a difference of greater
magnitude.
3. Results
A total of 1520 patients were recruited in the two study centers
in order to select 60 participants. The study was conducted in a tertiary referral center and the high rate of screen failure was due to
the fact that in addition to experiencing menopausal symptoms, the
patients frequently had associated pathologies. This hampered the
inclusion process and resulted in the enrollment period having to be
extended in order to achieve a total of 60 eligible subjects. Women
receiving care at outpatient menopause clinics were invited to complete a check list to verify whether they met the admission criteria
for the study. The majority of women screened were excluded
because they did not meet these criteria (95%) or because they had
no interest in participating in the study (5%). Most (n = 1370) were
excluded at the first pre-randomization visit, the main reasons for
exclusion being: hypertension (54%); obesity (40%); hysterectomy
(28%); metabolic syndrome (22%); diabetes mellitus (8%); having
some form of gynecological cancer (30%) or being on hormone or
non-hormonal therapy for menopausal symptoms (40%). Note that
some patients had more than one of the aforementioned conditions.
At the second pre-randomization visit, 90 women were considered ineligible for the following reasons: increased endometrial
thickness, abnormalities detected at mammography, estradiol level
>20 pg/ml and elevated lipid profile and/or fasting glucose levels
requiring immediate treatment with specific drugs. At the randomization visit, the remaining 60 women were allocated in equal
numbers to the three groups, as shown in Fig. 1. These groups were
followed-up for 16 weeks, compliance was high and no patients
discontinued or were lost to follow-up.
Table 1 shows the baseline characteristics of the participants
according to treatment group. There were no statistically significant differences in baseline characteristics between the groups.
The mean age of the patients was 52.4 years (SD 3.9). Women had
been postmenopausal for a mean of 4.1 ± 3.3 years and mean age
at menopause was 48 ± 3.7 years. With respect to education level,
the mean number of years of schooling was 6.8 ± 4.1 years. It is
important to emphasize that there were no statistically significant
differences between the three groups with respect to overall MRS
or MRS subscales at baseline.
A statistically significant decrease in overall baseline MRS score
and in the scores for all the MRS subscales was found after 16 weeks
of treatment in all the groups (intragroup differences) except for
the urogenital subscale in which no improvement was found in the
placebo group. Intergroup analysis revealed a statistically significant improvement in somatic and urogenital symptoms only in
the HT and soy groups. There was no difference between the study
groups with respect to psychological symptoms or total MRS score,
all three groups showing a similar improvement (Table 2).
Mean percentage variations in the psychological, somatic and
urogenital symptoms, respectively, of the Menopause Rating Scale,
are shown in Figs. 2–4 together with their respective standard deviations and according to treatment group. There was a significant
improvement in hot flashes, joint and muscle pain and vaginal dryness in the hormone therapy and soy groups compared with the
placebo group.
As expected, there was a statistically significant decrease of 46%
in the mean percentage variation in FSH levels and an approxi-
L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
265
Fig. 1. Flow chart of the study participants.
mately 5-fold increase in 17␤-estradiol levels from the mean levels
recorded at baseline only in the HT group. In the groups using soy
and placebo, there was no change in FSH and estradiol plasma levels
(Table 3).
There were no statistically significant differences in endometrial
thickness between the three groups at baseline and after 16 weeks
of treatment (Table 4).
Data on vaginal cytology showed that maturation value were
similar in all studied groups at baseline. After 16 weeks of treatment
there was a significantly increased in maturation value only in the
HT group (Table 5).
There were no statistically significant differences in
the adverse effects evaluated (mastalgia, vaginal bleeding,
allergy, headache, nausea, weight gain, water retention and
Table 1
Characteristics of the women according to study group (n = 60).
Characteristics
Mean age (years ± SD)
Age at menopause (years)
Median (Q1 –Q3 )
Time since menopause (years)
Median (Q1 –Q3 )
Education (years of schooling ± SD)
Skin color (%)
White
Non-white
Parity (%)
≤2
>2
Social status (%)
Classes A/B
Classes C/D/E
Smoking habits (%)
Current smoker/ex-smoker
Never-smoker
Body mass index (kg/m2 )
Median (Q1 –Q3 )
MRS (±SD)
Total score
Psychological score
Somatic score
Urogenital score
Q1 , first quartile; Q3 , third quartile.
a
ANOVA test.
b
Kruskal–Wallis non-parametric test.
c
Chi-square test.
d
Fisher’s exact test.
Groups
HT
Soy
Placebo
p-Value
53.3 ± 4.5
48.0
(47.0–50.5)
5.6
(1.5 – 10)
6.6 ± 4.2
52.9 ± 3.5
49.0
(47.5–50.5)
2.5
(1.5 – 4.0)
7.6 ± 4.4
50.9 ± 3.4
48.0
(46.0–50.0)
2.5
(1.0 – 5.5)
6.3 ± 3.9
0.10a
0.43b
65.0
35.0
40.0
60.0
70.0
30.0
0.11c
45.0
55.0
65.0
35.0
40.0
60.0
0.33d
40.0
60.0
55.0
45.0
45.0
55.0
0.62c
60.0
40.0
25.9
(24.0 – 28.5)
35.0
65.0
26.4
(24.2 –28.8)
45.0
55.0
26.6
(24.1 – 30.0)
0.61c
24.9 ± 6.2
9.9 ± 3.8
9.7 ± 2.4
5.4 ± 2.1
21.6 ± 7.7
8.4 ± 4.3
8.5 ± 2.9
4.8 ± 2.2
20.7 ± 7.6
7.3 ± 4.4
8.9 ± 2.3
4.6 ± 2.8
0.13b
0.73a
0.32b
0.16a
0.15a
0.06a
0.55a
266
L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
Table 2
Mean overall Menopause Rating Scale score and subscale scores at baseline and after 16 weeks of treatment and percentage variation according to treatment group (n = 60).
Menopause Rating Subscale
Psychological symptoms
HT
Soy
Placebo
Somatic symptoms
HT
Soy
Placebo
Urogenital symptoms
HT
Soy
Placebo
Total
HT
Soy
Placebo
Baseline mean (SD)
16 weeks mean (SD)
p-Value* intragroup
differences
Change (%) intergroup
differences
p-Value** intergroup
difference
9.9 (3.8)
8.4 (4.3)
7.3 (4.4)
6.5 (3.4)
4.9 (3.8)
4.8 (3.3)
<0.01
<0.01
0.01
−30.1
−39.8
−22.1
0.61
9.7 (2.4)
8.5 (2.9)
8.9 (2.3)
4.4 (2.9)
3.9 (2.9)
6 (2.8)
<0.01
<0.01
<0.01
−45.6
−49.8
−28.6
0.02
5.4 (2.1)
4.8 (2.1)
4.6 (2.8)
3 (1.7)
3.3 (2.3)
3.9 (2.2)
<0.01
<0.01
0.22
−38.6
−31.2
5.7
0.04
24.9 (6.2)
21.6 (7.6)
20.7 (7.6)
13.8 (5.9)
12.1 (7.9)
14.7 (6.6)
<0.01
<0.01
<0.01
−40.9
−44.1
−23.4
0.06
Somatic symptoms: HT × soy = 0.80; HT × placebo < 0.01; soy × placebo = 0.03.
Urogenital symptoms: HT × soy = 0.53; HT × placebo = 0.01; soy × placebo = 0.01.
*
p-Values for intragroup differences (paired Student’s t test).
**
p-Values for intergroup differences (Kruskal–Wallis test followed by Mann–Whitney for multiple comparisons).
Table 3
Mean percentage variation (CI 95%) of FSH and estradiol according to the treatment group (n = 60).
Variable
HT
Soy
Placebo
p
FSH
Estradiol
−46.2 (−62.3; −30)
513.7 (208.2; 819.3)
9.0 (−7.7; 25.7)
52.31 (19.3; 123.9)
3.3 (−24.8; 31.4)
22.0 (−9.3; 55.2)
<0.01*
<0.01**
*
**
ANOVA test (followed by Tukey).
Non-parametric Kruskal–Wallis test (followed by Mann–Whitney).
Table 4
Changes in endometrial thickness at baseline and after 16 weeks of treatment according to treatment group (n = 60).
Mean endometrial thickness (mm)
Baseline
Post-treatment
*
p*
Mean (SD)
HT
Soy
Placebo
3.2 (±1.3)
3.8 (±1.6)
4.2 (±2.3)
4.1 (±2.0)
3.9 (±2.2)
3.5 (±2.6)
0.11
0.16
Kruskal–Wallis test.
Table 5
Changes in vaginal maturation value at baseline and after 16 weeks of treatment according to treatment group (n = 60).
Mean maturation value
Baseline
Post-treatment
*
p*
Mean (SD)
HT
Soy
Placebo
41.2 (±23.4)
59.3 (±11.8)
41.9 (±23.6)
41.3 (±22.6)
43.3 (±27.2)
46.6 (±25.6)
0.96
<0.01
Kruskal–Wallis test.
intestinal complaints) between the three treatment groups
(Table 6).
4. Discussion
Fig. 2. Mean percentage variation in the psychological symptoms subscale of
the Menopause Rating Scale according to treatment group. Change from baseline
(Kruskal–Wallis test followed by the Mann–Whitney test).
The principal objective of this study was to compare the effects
of hormone therapy, dietary soy supplementation and placebo on
the treatment of menopausal symptoms over a 16-week period. All
three treatments were found to be effective in relieving psychological, somatic and urogenital symptoms. The only difference that
was not statistically significant between baseline measurements
and those recorded after 16 weeks of treatment referred to the
urogenital symptoms in women in the placebo group. When the
percentages of improvement were compared between the groups,
hormone therapy and dietary soy supplementation were found to
be significantly more effective in improving somatic symptoms
(hot flashes and joint and muscle pain) and urogenital symptoms
L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
Fig. 3. Mean percentage variation in the somatic symptoms subscale of the
Menopause Rating Scale according to treatment group. Change from baseline
(Kruskal–Wallis test followed by the Mann–Whitney test).
(vaginal dryness) compared to the placebo. With respect to the
percentage of improvement in psychological symptoms, no statistically significant difference was found between the three treatment
groups.
In this study, isoflavone reduced the incidence of hot flashes.
Some factors may have contributed towards these findings, such
as the proportion of isoflavone and soy protein contained in the
dietary supplement evaluated in the present study, which consisted of 3.75 mg/gram of soy protein (45 mg total isoflavone/12 g
of soy protein), considered intermediate sources of isoflavones
[15]. The richest source of isoflavone is soy protein (with 1–3 mg
of soy protein isoflavone/gram), which was used in this study
[16]. Another possibility that may explain these differences is
the severity of hot flashes at baseline, since in some trials
women with less severe symptomatology were eligible for participation [17]. In the present trial, the symptomatology was
considered adequate, with a similar overall baseline MRS score in
all three groups and symptoms that were considered moderate to
severe.
267
Fig. 4. Mean percentage variation in the urogenital symptoms of the Menopause
Rating Scale according to treatment group. Change from baseline (Kruskal–Wallis
test followed by the Mann–Whitney test).
Some critics may question the duration of soy isoflavone use and
think that it is too short to elicit a satisfactory clinical response.
However, most authors have observed that the most significant
effect on the relief of climacteric symptom occurred within the initial short period of isoflavone exposure, usually within 12 weeks
of treatment. Therefore, the 16-week long period of intervention
was satisfactory to induce effects on climacteric symptoms [1,17].
The literature is highly controversial about the isoflavone dose
used. Therefore, it was reasonable that the dose be based on two
aspects: the source of isoflavone, as discussed above and bibliographic review of efficiency and safety profile. Most authors use
a dose of isoflavone between 40 and 100 mg/day showing an adequate efficiency and safety profile [1,17].
One of the most common and most bothersome menopausal
symptoms is joint/muscle pain. These symptoms improved significantly in both the HT and soy groups by around 30% and
40%, respectively. Several agents derived from plants including
genistein (soy) suppress the expression of tumor necrosis factoralpha, interleukin-1 beta, interleukin-6 and nuclear factor-kappa
B, attenuating the cell-mediated immune response and therefore
Table 6
Percentage distribution of side effects during the treatment period, according to the study group (n = 60).
Side effects
Mastalgia
Presenting symptom
Other condition
Bleeding
Presenting symptom
Other condition
Skin problem-allergy
Presenting symptom
Other condition
Headache
Presenting symptom
Other condition
Nausea
Presenting symptom
Other condition
Weight gain
Presenting symptom
Other condition
Water retention
Presenting symptom
Other condition
Intestinal complaints
Presenting symptom
Other condition
*
Fisher’s exact test.
HT
Soy
n
%
n
3
17
15.0
85.0
2
18
4
16
20.0
80.0
1
19
p*
Placebo
%
n
%
10.0
90.0
0
20
0.0
100.0
1
19
5.0
95.0
1
19
5.0
95.0
5.0
95.0
0
20
0.0
100.0
0
20
0.0
100.0
2
18
10.0
90.0
1
19
5.0
95.0
0
20
0.0
100.0
4
16
20.0
80.0
0
20
0.0
100.0
3
17
15.0
85.0
4
16
20.0
80.0
3
17
15.0
85.0
5
15
25.0
75.0
3
17
15.0
85.0
3
17
15.0
85.0
1
19
5.0
95.0
2
18
10.0
90.0
1
19
5.0
95.0
1
19
5.0
95.0
0,35
0.44
0.33
0.76
0.14
0.92
0.68
1.00
268
L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
diminishing the inflammatory response [18,19]. Genistein exerts
an evident anti-inflammatory property. This ability to modulate
the expression of proinflammatory signals clearly suggests that
soy could potentially be used in the treatment of some form of
pain-related joint disorder [20].
In the Menopause Rating Scale’s sub-item related to urogenital
symptoms, a significant improvement occurred in vaginal dryness
in the HT group and to a lesser extent in the soy group. We cannot infer that improvement in vaginal dryness according to the
MRS in the group using soy was due to a direct action of phytohormone on the vaginal mucosa because we did not find any
increase in the vaginal maturation value in the soy group during the treatment period of 16 weeks. The literature is actually
controversial concerning this aspect. In a randomized controlled
trial carried out for 6 months with 187 women, Chiechi et al. [21]
found that a soy rich diet (isoflavone 20–30 mg/day) effectively
increases the maturation indices of vaginal cells and should be considered as a therapeutic option to avoid vaginal atrophy in the
postmenopause. On the other hand, a randomized double-blind
clinical trial conducted in 79 women using 120 mg of isoflavone
for 6 months reported that soy isoflavone had no effect on vaginal
mucosa [22]. Nahas et al [8] conducted a double-blind, randomized, placebo-controlled study with 80 women using 100 mg of
isoflavone for 10 months. Furthermore, these authors reported that
neither soy isoflavone nor placebo exerted any meaningful effect on
vaginal maturation values. Regarding sexual and bladder problems,
no treatment was found to have any effect [23].
Psychological symptoms improved in a similar manner in the
three treatment groups. This finding differs from results published
in the literature in which no improvement is seen in psychological symptoms with either hormone therapy or phytotherapy [24].
Another set of factors that may have contributed to improving psychological symptoms in all the study groups refers to the positive
psychological factors usually associated with the touching, caring
and attention that are provided with medical care. In addition to
the positive effects generated directly, psychological factors may
also have enhanced patient motivation regarding self-care.
On the particular clinical issue of the relief of menopausal symptoms, randomized placebo-controlled trials have demonstrated the
efficacy of various HT regimes, but also often an apparently very
potent placebo effect. In the updated Cochrane Collaboration Systematic Review of 24 trials involving 3329 participants, there was
a 75% overall reduction (95% CI: 64–82%) in hot flashes with oral
estrogen, but also a 57% reduction (95% CI: 45–67%) with placebo
[25]. Many factors will affect the subject’s response to a placebo
including the information provided on the potential benefits of the
study drug, a prior belief in the effectiveness of therapy, the duration of the study, frequency of follow-up, natural history of the
condition, a natural regression towards the mean, patient compliance and involvement, and clinical settings, among other factors
[26].
With the objective of assessing the effect of dietary soy supplementation on endocrine function, FSH and 17␤-estradiol levels
were measured at baseline and after 16 weeks of treatment. In the
group using soy, there was no change in FSH and estradiol plasma
levels during the study period. In agreement with this finding, an
extensive review on the effect of soy on FSH and estradiol levels
concluded that no significant effect was observed [27].
There was no significant change in endometrial thickness during the treatment period in the studied groups. These data suggest
that isoflavone treatment is not sufficient to produce a proliferative effect on endometrial tissue. This finding is in line with other
investigations [8,11]. HT did not cause any change in endometrial
thickness probably due to the low-dose used in this study.
The adverse effects measured in this trial were not significant,
which is in agreement with most of the literature reviewed. All
the treatment modalities were well-accepted and this may have
contributed towards the absence of dropouts in this study. In the
Cochrane Review of 2007, most trials revealed no significant difference between randomized groups [17]. It is important to emphasize
that, in this trial, the incidence of mastalgia and bleeding was similar in the soy and HT groups, probably because the type of hormone
therapy used was low-dose. The evidence from human studies
does not suggest any worrisome adverse events beyond mild gastrointestinal intolerance; however, conclusions are limited due the
heterogeneity of soy products and their different formulations used
in the different studies [17,28].
This study elected to use the MRS, which is a self-administered,
health-related quality of life (HRQoL) scale that seeks to diminish
errors made by health professionals when applying questionnaires [13,29]. Moreover, the MRS is widely used and provides a
quantitative evaluation of menopausal symptoms that allows the
assessment of symptomatology, the success of the various treatments and comparison of symptoms to be evaluated over time [30].
The MRS has been validated for use in many cultures and in different
social classes [30]. The Portuguese language version was developed
in Brazil following international methodological recommendations
for the linguistic and cultural adaptation of HRQoL instruments
[30].
A possible limitation of this study is that phytoestrogen excretion analysis was not performed and the compliance was assessed
only according to patient self-report and the number of product
packets missed.
This randomized, double-blind, placebo-controlled trial provides preliminary evidence of a possible beneficial effect of a
dietary soy supplement containing 90 mg of isoflavone/day and
of low-dose hormone therapy in the management of menopausal
symptoms such as hot flashes, muscle/joint pain and vaginal
dryness in postmenopausal women. We believe that the most
crucial measure for managing a climacteric woman is individualization and adequate orientation to her needs in the
present and future. The attending professional should be sensitive and capable of providing general and specific measures for
the maintenance of a woman’s health status and general wellbeing.
5. Conclusion
Using a well-validated measurement tool, this study provides
further evidence that soy-based phytoestrogen (90 mg of isoflavone
per day) and low-dose hormone therapy both improve the severity
of hot flashes, joint/muscle pain and vaginal dryness. This study has
been performed with an intention-to-treat analysis and adequate
power to answer the question concerning the purpose of this study.
The intake of isoflavones was accomplished with food as part of
normal daily intake. Since many women choose not to undergo
hormone therapy, the superiority of isoflavone over placebo may
be useful to them.
Contributors
Lucio Omar Carmignani participated in all steps of this research,
elaborating the project, data collection and article redaction. Adriana Orcesi Pedro participated in the project elaboration, data
collection and article redaction. Aarão Mendes Pinto-Neto participated supervising the data collection and reviewing the article.
Lucia Costa-Paiva participated elaborating the project and the article redaction.
L.O. Carmignani et al. / Maturitas 67 (2010) 262–269
Competing interest
The authors have no conflicts of interest.
Funding
This study received funding from the São Paulo Foundation for
the Support of Research (FAPESP), grant # 03/04464-0.
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